Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors

Introduction The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development. Methods To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice. Results Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching. Conclusions Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.National Cancer Institute (U.S.). Integrative Cancer Biology Program (grant U54 CA112967)Virginia and D.K. Ludwig Fund for Cancer Researc

Datopotamab–deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379

Revival and Recharacterization of a Preclinical Model of Hormone-Dependent Breast Cancer to Study Immunotherapy

Abstract Immune checkpoint inhibitors have yet to significantly improve outcomes for hormone-dependent estrogen/progesterone receptor–positive breast cancer. To address this issue, there is a need for murine models that more closely mimic hormone receptor–positive breast cancer. In this issue, Gil Del Alcazar and colleagues provide an in-depth characterization of a Nitroso-N-methylurea–induced mammary tumor model in outbred Sprague-Dawley rats that meets these needs as it mimics the heterogeneity for mutational profiles, estrogen receptor expression, and immune evasive mechanisms observed in human breast cancer. See related article by Gil Del Alcazar et al., p. 680 (1).</jats:p

Genetic analysis of the diabetes-prone C57BLKS/J mouse strain reveals genetic contribution from multiple strains

AbstractThe C57BLKS/J (BKS) inbred mouse strain is a widely used animal model of type 2 diabetes. In the presence of the diabetes (db) mutation, obese BKS-db mice develop severe diabetes. Genetic studies of diabetes-susceptibility in this strain are facilitated by the fact that BKS is a genetic composite between the diabetes-resistant C57BL/6J (B6) and susceptible DBA/2J (DBA) strains. On this basis, it has been hypothesized that diabetes-susceptibility in BKS is conferred by DBA-derived alleles. However, recent studies revealed non-B6/non-DBA genetic material in BKS. To identify the origin of this genetic component, we generated a genomic map of BKS using 537 microsatellite markers. Our results demonstrate that, in addition to B6 and DBA, BKS contains alleles from at least three other strains, including 129, C57BL/10 and an unidentified mouse strain. We also analyzed two congenic strains, B6-db and BKS-db, which are widely used for the genetic mapping of diabetes-susceptibility loci. We identified several donor-derived genomic regions introduced during the generation of these congenic strains. In summary, our study reveals novel aspects of the genetic fine-structure of BKS and related strains and facilitates the identification of diabetes-susceptibility loci in this mouse model

Lymph Node Immune Profiles as Predictive Biomarkers for Immune Checkpoint Inhibitor Response

The need for predictive biomarkers that can accurately predict patients who will respond to immune checkpoint inhibitor (ICI) immunotherapies remains a clinically unmet need. The majority of research efforts have focused on expression of immune-related markers on the tumour and its associated tumour microenvironment (TME). However, immune response to tumour neoantigens starts at the regional lymph nodes, where antigen presentation takes place and is regulated by multiple cell types and mechanisms. Knowledge of the immunological responses in bystander lymphoid organs following ICI therapies and their association with changes in the TME, could prove to be a valuable component in understanding the treatment response to these agents. Here, we review the emerging data on assessment of immunological responses within regional lymph nodes as predictive biomarkers for immunotherapies.</jats:p

Myeloid-derived suppressor cell dynamics control outcomes in the metastatic niche

AbstractMyeloid-derived suppressor cells (MDSCs) play a prominent and rising role in the tumor microenvironment. An understanding of the tumor-MDSC interactions that influence disease progression is critical, and currently lacking. To address this, we developed a mathematical model of metastatic growth and progression in immune-rich tumor microenvironments. We model the tumor-immune dynamics with stochastic delay differential equations, and study the impact of delays in MDSC activation/recruitment on tumor growth outcomes. We find when the circulating level of MDSCs is low, the MDSC delay has a pronounced impact on the probability of new metastatic establishment: blocking MDSC recruitment can reduce the probability of metastasis by as much as 50%. We also quantify the extent to which decreasing the immuno-suppressive capability of the MDSCs impacts the probability that a new metastasis will persist or grow. In order to quantify patient-specific MDSC dynamics under different conditions we fit individual tumors treated with immune checkpoint inhibitors to the tumor-MDSC model via Bayesian parameter inference. We reveal that control of the inhibition rate of natural killer cells by MDSCs has a larger influence on tumor outcomes than controlling the tumor growth rate directly. Posterior classification of tumor outcomes demonstrates that incorporating knowledge of the MDSC responses improves predictive accuracy from 63% to 82%. Our results illustrate the importance of MDSC dynamics in the tumor microenvironment and predict interventions that may shift environments towards a less immune-suppressed state. We argue that there is a pressing need to more often consider MDSCs in analyses of tumor microenvironments.</jats:p

Lymph Node Immune Profiles as Predictive Biomarkers for Immune Checkpoint Inhibitor Response

The need for predictive biomarkers that can accurately predict patients who will respond to immune checkpoint inhibitor (ICI) immunotherapies remains a clinically unmet need. The majority of research efforts have focused on expression of immune-related markers on the tumour and its associated tumour microenvironment (TME). However, immune response to tumour neoantigens starts at the regional lymph nodes, where antigen presentation takes place and is regulated by multiple cell types and mechanisms. Knowledge of the immunological responses in bystander lymphoid organs following ICI therapies and their association with changes in the TME, could prove to be a valuable component in understanding the treatment response to these agents. Here, we review the emerging data on assessment of immunological responses within regional lymph nodes as predictive biomarkers for immunotherapies.</p

Best Foot Forward: Neoadjuvant Systemic Therapy as Standard of Care in Triple-Negative and HER2-Positive Breast Cancer

Neoadjuvant systemic treatment of early-stage breast cancer has been used to improve resectability and reduce the extent of breast and axillary surgery. More recently, several other merits of neoadjuvant systemic treatment have emerged, including the ability to tailor clinically available adjuvant systemic therapy options based on pathologic response and to serve as a platform for early assessment of novel agents and response biomarkers and as an avenue for treatment optimization investigations (local and systemic therapy escalation and de-escalation trials guided by pathologic response). Attainment of a pathologic complete response (pCR) is associated with excellent long-term outcomes; conversely, the presence of residual disease is associated with a high risk of recurrence for patients with HER2-positive breast cancer and triple-negative breast cancer (TNBC). Treatment strategies in early-stage HER2-positive breast cancer include regimens incorporating trastuzumab, pertuzumab, ado-trastuzumab emtansine, and neratinib, resulting in high pCR rates and overall excellent long-term outcomes. Currently available cytotoxic regimens yield pCR for 35% to 55% of patients with TNBC, and immune checkpoint inhibition is showing early promise for this subtype. New drug and predictive biomarker evaluations in the neoadjuvant setting aim to develop optimal treatment strategies for the individual patient, with the ultimate goal of maximizing efficacy and minimizing toxicity. Research efforts involving novel agents are being undertaken to address the high risk of recurrence for patients with residual disease. Omission of breast surgery following neoadjuvant chemotherapy requires further development of imaging and biopsy techniques to accurately assess the extent of residual disease before clinical application.</jats:p